担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanisms of fibrosis onset and development remain to be elucidated. However, it has been reported that mechanical stretch promotes fibrosis in various organs and cells, and may be involved in the pathogenesis of pulmonary fibrosis. We demonstrated that ventilator-induced lung hyperextension stimulation in mice increased the expression of connective tissue growth factor (CTGF), a profibrotic cytokine, in lung tissue. Increased CTGF expression induced by cyclic mechanical stretch (CMS) was also observed in vitro using A549 human alveolar epithelial cells. Pathway analysis revealed that the induction of CTGF expression by CMS involved MEK phosphorylation. Furthermore, early growth response 1 (Egr-1) was identified as a transcription factor associated with CTGF expression. Finally, the antifibrotic drug pirfenidone significantly reduced CTGF expression, MEK phosphorylation, and Egr-1 levels induced by CMS. Thus, our results demonstrated that profibrotic cytokine CTGF induced by CMS may be a therapeutic target of pirfenidone.

DOI： 10.1016/j.resp.2023.104142

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sarcoidosis is a multisystem disease with an unknown etiology and is characterized by the formation of noncaseating granulomas in the affected organs. We present the case of a 69-year-old male Japanese patient with bilateral hilar lymphadenopathy on chest radiographs for more than 10 years, left without further investigation. The patient reported no clinical symptoms. Chest computed tomography revealed ground-glass opacities and reticular shadows in both lungs, along with bilateral hilar and mediastinal lymphadenopathy. Lymphocytosis was observed in bronchoalveolar lavage fluid. Pathological examination of transbronchial lung biopsy revealed noncaseating, epithelioid granulomas congruous with sarcoidosis, together with other findings. There were no abnormalities on electrocardiogram, echocardiogram, and ophthalmic examination.For progressive dyspnea on exertion, systemic corticosteroid therapy with oral prednisolone (25 mg/day) was initiated in 2017 and gradually tapered. Despite this intervention, the decline in forced vital capacity (FVC) was accelerated. Three years later, the patient noticed swelling in his right wrist. Further investigation revealed elevated anti-cyclic citrullinated peptide antibodies and absence of noncaseating epithelioid granuloma on surgical biopsy, leading to the diagnosis of rheumatoid arthritis (RA). Thereafter, the anti-fibrotic agent nintedanib was initiated, because interstitial lung disease (ILD) was considered to have converted into a progressive fibrosing phenotype (PF-ILD) with overlapping RA-associated lung involvement. With treatment, the progression of decline in FVC was slowed, although home oxygen therapy was introduced.

DOI： 10.1177/17534666231158279

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記述言語：英語  

Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein presented two cases. Case 1: 53-year-old man with Crohn's disease treated with mesalazine and azathioprine. Pulmonary nodular shadows were incidentally detected on chest imaging, and revealed granulomas through transbronchial lung biopsy. Case 2: 68-year-old man with ulcerative colitis treated with mesalazine. He presented with fever and respiratory symptoms, and chest imaging showed multiple nodular infiltrates. He was diagnosed with organizing pneumonia by lung biopsy. Both cases were diagnosed to have pulmonary involvement associated with inflammatory bowel disease (IBD) according to multidisciplinary examination including positron emission tomography-computed tomography (FDG-PET) and pathological test. Pulmonary manifestations with IBD may not always require discontinuation of drugs or additional use of steroids or immunosuppressants.

DOI： 10.1016/j.rmcr.2023.101914

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.

DOI： 10.1038/s41598-022-24406-z

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis.

DOI： 10.1038/s41467-022-33160-9

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例は23歳女性。シェーグレン症候群に対して免疫抑制薬を長期内服中であった。2ヵ月前から倦怠感、発熱、腰痛を認め、全身精査で肺野に活動性病変を認めず、全身リンパ節、骨、皮下、腹膜、腸管に多彩な病変を認めた。インターフェロンγ遊離試験(interferon gamma release assay:IGRA)は陰性であった。縦隔リンパ節生検から結核菌が培養され、播種性結核と診断した。免疫抑制宿主において、複数の病変を認める際は、IGRAが陰性で活動性肺病変を認めない場合でも、播種性結核を念頭におく必要がある。(著者抄録)

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Following COVID-19 vaccination, ipsilateral axillary and cervical lymphadenopathy may occur, called vaccine-related hypermetabolic lymphadenopathy, which is considered reactive lymphadenopathy. We report here a case of Kikuchi-Fujimoto disease, which occurred three months after vaccination with COVID-19 vaccine. The patient had cervical and axillary lymph node enlargement and a short-term fever that resolved spontaneously after the first and second vaccines. On the 90th day after the first vaccination, the patient developed a high fever and pathologically diagnosed necrotizing lymphadenitis in the axilla, which was diagnosed as Kikuchi-Fujimoto disease. Gallium scintigraphy showed localized swelling and strong uptake in the ipsilateral axilla. It implies the possibility of Kikuchi-Fujimoto Disease in axillary drainage lymph nodes in association with COVID-19 vaccine. Although only a few cases have been reported so far, this case is novel because of its later onset and diagnosis based on pathological and gallium scintigraphy imaging findings.

DOI： 10.1080/21645515.2022.2071080

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器内視鏡学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although corticosteroids are expected to be a candidate therapy for coronavirus disease 2019 (COVID-19) through the suppression of cytokine production, the efficacy in non-severe patients who do not require supplemental oxygen remains controversial. The aim of this study was to investigate the efficacy of corticosteroid therapy for non-severe patients. METHODS: We performed a retrospective observational study for 10 patients with non-severe COVID-19 who received corticosteroid therapy at our institute between July 1, 2020, and January 31, 2021. RESULTS: The median age of the 10 patients was 60 years, and nine patients were male. Nine of the 10 patients had multiple comorbid conditions (e.g., hypertension, diabetes and obesity). Although blood oxygen saturation was maintained above 95%, all patients showed persistent fever and deterioration of their chest imaging findings. Thus, we decided to initiate corticosteroid treatment. The median duration from the onset of symptoms to the initiation of corticosteroid therapy was eight days. All patients used dexamethasone (6 mg/day) as corticosteroid therapy, and the median period was 7.5 days. After the start of corticosteroid therapy, all patients showed a rapid clinical improvement, and no patients showed severe progression. CONCLUSION: The latest World Health Organization guidance recommends against corticosteroid treatment for non-severe patients. In this report, we showed that the early administration of corticosteroids during the non-critical phase, when oxygen supplementation is not required, was useful for the early improvement and prevention of severe disease in patients with risk factors for severe COVID-19 and worsening clinical symptoms.

DOI： 10.1272/jnms.JNMS.2022_89-409

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語  

A 59-year-old woman complaining of wet cough, hemoptysis, slight fever, anorexia, and malaise was admitted to hospital with suspected lobar pneumonia. She received treatment for myocardial infarction and deep venous thrombosis caused by familial protein C deficiency. Rapid deterioration due to respiratory failure occurred despite intensive care with broad-spectrum antibiotics. At a later date, sputum examination revealed the presence of Aspergillus niger. Based on clinical and autopsy findings, she was diagnosed with acute respiratory failure due to pulmonary aspergillosis with acute fibrinous and organizing pneumonia. This is the first reported case of pulmonary aspergillosis with acute fibrinous and organizing pneumonia complicated by calcium oxalate resulting from Aspergillus niger infection, leading to severe inflammation and tissue injury in the lungs.

DOI： 10.1016/j.rmcr.2022.101641

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited. METHODS: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records. RESULTS: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax). CONCLUSIONS: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.

DOI： 10.1016/j.resinv.2021.04.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The role of inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) is unclear. Hence, this study aimed to evaluate the efficacy of ICS as an add-on to long-acting muscarinic antagonist (LAMA)/long-acting beta 2 agonist (LABA), which was assessed using the impulse oscillation system (IOS), in patients with COPD. Methodology We included patients with COPD whose treatment was changed from LAMA/LABA (≥four weeks) to ICS/LAMA/LABA between April 2019 and March 2021. To gain insight into the effect and safety of ICS-containing triple therapy for COPD, pulmonary function; Short-Form 36, St. George's Respiratory Questionnaire, COPD Assessment Test, and modified Medical Research Council scores; and airway resistance assessed using the IOS from one week before LAMA/LABA was switched to ICS/LAMA/LABA therapy until more than eight but less than twelve weeks after switching were evaluated. Results In total, 46 patients with COPD (mean age: 72.28 ± 7.81 years) were included in the study. None of the pulmonary function test parameters significantly changed from baseline values (mean difference in forced expiratory volume in one second [FEV1.0]: +0.032, P = 0.12; percentage FEV1.0 [FEV1.0%]/forced vital capacity [FVC]: -0.58, P = 0.42; and FVC: +0.087, P = 0.058). Meanwhile, the IOS showed that resonant frequency (mean difference from baseline: -2.12, P < 0.0001) and bodily pain scores in the St. George's Respiratory Questionnaire (mean difference: -7.03, P = 0.031) significantly decreased. Conclusions Switching from LAMA/LABA to ICS/LAMA/LABA therapy reduces airway elasticity-to-inertial resistance ratios, which may lead to structural airway improvements in patients with COPD.

DOI： 10.7759/cureus.19168

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記述言語：英語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1-induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

DOI： 10.1016/j.yexcr.2020.112416

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an Expert Central Review Committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87%) patients, and of those, 172 (83.1%) patients responded well and survived, and 35 (16.9%) died (most died during corticosteroid treatment). Nine patients experienced a relapse; at the time of relapse, 4 patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, 3 of 4 patients were taking low doses or had nearly completed dose tapering. All patients (except one whose treatment was unknown) received corticosteroids for the treatment of relapse, but 1 patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.

DOI： 10.1111/cas.14715

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This post-marketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an Expert Central Review Committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from start of nivolumab treatment to onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, 3 had peritumoral-GGO, and 5 had a change in radiographic pattern from non-DAD at onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.

DOI： 10.1111/cas.14710

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Measuring lung compliance is useful for evaluating interstitial lung disease (ILD) progression because reduced lung compliance by fibrosis progression is the main primary cause of decreased vital capacity. However, because of the invasiveness of the method, requiring the insertion of a balloon into the esophagus, lung compliance is rarely measured. A recently developed, possible method estimates intrathoracic pressure using fingertip photoplethysmography. This method non-invasively measures the lung dynamic compliance (Cdyn) by simultaneously measuring tidal volume. We evaluated the efficacy of this method in assessing ILD. METHODS: We conducted a single-center, observational cross-sectional study to evaluate the efficacy of this method in subjects with ILD as compared with that in healthy control subjects. The main outcome was the estimated Cdyn (eCdyn) determined using this method. We also evaluated potential confounding factors of eCdyn in the baseline characteristics. RESULTS: In the ILD group (n = 14) the median eCdyn was significantly lower than that in the control group (n = 49) (0.122 vs. 0.183; P = 0.011). In univariate regression analysis, eCdyn was significantly correlated with height, weight, forced vital capacity, forced expiratory volume in one second, diffusing capacity for carbon monoxide, and usual interstitial pneumonia (UIP). In multivariate regression analysis, both weight (β = 0.49, P = 0.011) and UIP (β = 0.52, P = 0.007) were significantly associated with eCdyn. CONCLUSIONS: We demonstrated a significant reduction in Cdyn in subjects with ILD using photoplethysmography. This non-invasive method might be a novel, promising tool for evaluating fibrosis progression in ILD.

DOI： 10.1272/jnms.JNMS.2021_88-411

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

DOI： 10.2169/internalmedicine.5435-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Using real-world Japanese post-marketing data, we characterized interstitial lung disease (ILD) development during second- or later-line osimertinib treatment for epidermal growth factor receptor-mutation-positive non-small cell lung cancer. Retrospective radiologic image evaluation of patients developing ILD was also performed. METHODS: Patients who had ILD events reported as an adverse drug reaction by their physicians and were assessed as having developed ILD based on the judgement of an ILD expert committee in Japan were included. RESULTS: Among 3578 patients, 252 ILD events were reported in 245 (6.8%) patients by the attending physicians. The median (range) time to first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231/3578 patients (6.5%) as having ILD. Prior nivolumab therapy (adjusted odds ratio: 2.84; 95% confidence interval: 1.98-4.07) and history/concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received prior nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed with increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment. CONCLUSIONS: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. History/concurrence of ILD and history of prior nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

DOI： 10.1016/j.jtho.2020.08.025

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記述言語：日本語   出版者・発行元：(公社)日本化学療法学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Adverse drug reactions (ADRs) during real-world osimertinib use were investigated in Japan. METHODS: Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib per the Japanese package insert (80 mg once daily) were included. Data were collected between 28 March 2016 and 31 August 2018. RESULTS: The median observation period in the safety analysis population (n = 3578) was 343.0 days. ADRs (defined as adverse events whose causality to osimertinib could not be denied by the attending physicians or manufacturer) were reported in 58.1% (2079/3578) of patients. ADRs of interstitial lung disease events were reported in 6.8% (245/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, of whom 29 (11.8%) died (0.8% of patients overall). ADRs of QT interval prolonged, liver disorder and haematotoxicity were reported in 1.3% (45/3578; Grade ≥ 3, 0.1% [5/3578]), 5.9% (212/3578; Grade ≥ 3, 1.0% [35/3578]) and 11.4% (409/3578; Grade ≥ 3, 2.9% [104/3578]) of patients, respectively. In the efficacy analysis population (n = 3563), 119 (3.3%) patients had complete responses, 2373 (66.6%) had partial responses and 598 (16.8%) had stable disease. The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively. CONCLUSIONS: These data support the currently established benefit-risk assessment of osimertinib in this patient population.

DOI： 10.1093/jjco/hyaa067

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記述言語：英語  

BACKGROUND: Interstitial lung disease (ILD) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening adverse event. The purpose of this study was to evaluate whether the development of immune-related adverse events (irAEs), especially ILD, was associated with treatment efficacy and to research the features and risk factors of ILD in advanced non-small cell lung cancer (NSCLC). METHODS: Between December 2015 and November 2018, 130 advanced NSCLC patients were treated with nivolumab, pembrolizumab or atezolizumab. The patients were categorized into two groups (irAEs group or non-irAEs group). Subsequently, we divided the irAEs group into two groups based on the incidence of ILD (ILD group and irAEs-non-ILD group). Treatment efficacy and the characteristics of ILD were evaluated. RESULTS: A total of 39 (30%) patients developed irAEs. ILD was observed in 16 (12%) patients. Patients with ILD had a higher objective response rate (ORR) compared with irAEs-non-ILD patients and non-irAEs patients (63%, 43% and 22%, respectively). Median progression-free survival (mPFS) was 15.9 months in ILD patients, 5.4 months in irAEs-non-ILD patients and 3.3 months in non-irAEs patients (log-rank test, P = 0.033). Pre-existing interstitial pneumonia (IP) was an independent risk factor for ILD-induced ICIs (odds ratio [OR] 14.7; 95% confidence interval [CI]: 2.16-99.6, P = 0.006). CONCLUSIONS: ORR and PFS were significantly better in ILD patients than in irAEs-non-ILD and non-irAEs patients. Pre-existing history of IP was an independent risk factor for ILD-induced ICIs.

DOI： 10.1111/1759-7714.13364

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景.末梢肺病変に対するガイドシース併用気管支腔内超音波断層法(endobronchial ultrasonography with a guide sheath:EBUS-GS)を用いた肺生検(EBUS-GS-TBB)の有用性が示されているが、診断に影響を与える因子は明らかになっていない。目的.EBUS-GS-TBBの診断に影響を与える因子を明らかにすることを目的とした。方法.日本医科大学付属病院において2016年7月から2018年4月までにEBUS-GSを用いて肺生検が施行された118例の中で、最終的に確定診断が得られた101例を後方視的に検討した。EBUSのプローブの位置によって、エコー所見を'within'、'outside'、'broadly adjacent to'、'narrowly adjacent to'の4つに分類した。Adjacent toの中でプローブ周囲の180度以上360度未満の範囲に病変が描出されたものをbroadly adjacent toと新たに定義し、それ以外をnarrowly adjacent toと新たに定義した。結果.EBUS-GSによる確定診断率は78.2%であった。多変量解析にて、エコー所見がwithinまたはbroadly adjacent toの患者は診断率が有意に高かった(オッズ比4.25、P<0.01)。肺気腫を合併する患者では有意に診断率が低かった(オッズ比0.29、P=0.02)。検査前のthin-section CTにおけるbronchus sign陽性は診断に寄与する有意な因子であった(オッズ比6.86、P=0.03)。結論.EBUS-GS-TBBでは、エコー所見がbroadly adjacent toの場合でも診断率は高く、withinが得られない症例でもよりよいエコー描出を目指すべきである。肺気腫合併例は診断率が低い可能性があり、検査前の背景肺の評価も重要である。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1272/jnms.JNMS.2020_87-302

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.

DOI： 10.2217/fon-2019-0102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.

DOI： 10.1038/s41374-018-0158-9

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines. A 73-year-old female was admitted to our hospital due to dyspnea and the presence of an abnormal shadow on the chest roentgenogram. She had received treatment with numerous drugs, including the following herbal medicines: Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs. The bronchoalveolar lavage fluid was progressively bloody. In addition, culture did not show the presence of microorganisms in the fluid. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. Based on this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued the use of all previous agents, and received treatment with corticosteroids. Her respiratory condition and the chest roentgenogram improved. According to the timing of administration and rechallenge with other drugs, the herbal medicines were suspected to be the causative drugs. Among those, Seisin-renshi-in was the most suspicious. Firstly, Seisin-renshi-in contains Ougon (skullcap), which is known to cause pneumonitis. Secondly, a dr

DOI： 10.1272/jnms.JNMS.2019_86-504

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajic.2019.04.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1272/jnms.JNMS.2019_86-504

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. Methods: We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. Results: A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). Conclusion: Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

DOI： 10.1093/jjco/hyy180

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DOI： 10.1016/j.rmcr.2019.01.012

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DOI： 10.1272/jnms.JNMS.2019_86-8

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記述言語：英語  

Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients with

DOI： 10.1272/jnms.JNMS.2019_86-8

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記述言語：英語  

An 82-year-old man with a recurrence of pulmonary pleomorphic carcinoma was treated with pembrolizumab. He achieved partial response after three cycles of pembrolizumab. However, he developed febrile neutropenia. A bone marrow aspiration sample revealed a decrease of mature neutrophils, and anti-neutrophil antibody was detected in blood. Computed tomography scans revealed consolidation in the right lung. Pathological findings in lung biopsy tissue revealed organizing pneumonia. Pembrolizumab-induced agranulocytosis and interstitial lung disease (ILD) were diagnosed. We initiated antibacterial therapy and granulocyte colony-stimulating factor (G-CSF). The neutrophil count immediately increased, and the fever decreased. The improvement of ILD was achieved without using systemic steroids. Moreover, the patient developed ocular myasthenia gravis induced by pembrolizumab. This is the first case report of pembrolizumab-induced agranulocytosis. Agranulocytosis was improved by administration of G-CSF without using systemic steroids. However, further studies are needed to determine the optimal treatment for patients with anti-neutrophil antibody whose tumor has progressed.

DOI： 10.1093/omcr/omy094

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press  

Elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeted against signaling lymphocytic activation molecule F7 (SLAMF7), has recently been used in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. The clinical characteristics of drug-induced interstitial lung disease (ILD) due to elotuzumab have not been clarified. In this report, we describe a patient with refractory multiple myeloma who received elotuzumab in combination with lenalidomide and dexamethasone in whom fatigue, fever and diffuse pulmonary infiltration developed. The patient had a history of long-term therapy with lenalidomide without pulmonary toxicity. Bronchoscopy with bronchoalveolar lavage was negative for infection, and transbronchial lung biopsies showed active alveolitis with lymphocytic infiltration and myxomatous change of the thick alveolar wall. After the discontinuation of elotuzumab and lenalidomide, the patient's clinical symptoms gradually improved, and spontaneous remission of the pulmonary infiltration was observed. Based on the chest CT and lung pathology findings, the exclusion of infection and pulmonary edema, and according to the clinical course, we established a diagnosis of drug-induced ILD due to elotuzumab. Clinicians should bear in mind the potential for pulmonary toxicity in patients receiving elotuzumab-containing therapy.

DOI： 10.1093/jjco/hyy049

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4+CD25+FoxP3+ regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis. METHODS: C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully cauterized and the spleen was removed either on day 0 or 14 after BLM challenge. RESULTS: Splenocytes significantly ameliorated BLM-induced pulmonary fibrosis when they were administered on day 14. This effect was abrogated by depleting Tregs with an anti-CD25 monoclonal antibody. Adoptive transfer of Tregs on day 14 after a BLM challenge significantly attenuated pulmonary fibrosis, and this was accompanied by decreased production of fibroblast growth factor (FGF) 9-positive cells bearing the morphology of alveolar epithelial cells. In addition, BLM-induced plasma IL-10 expression reverted to basal levels after adoptive transfer of Tregs. Moreover, BLM-induced fibrocyte chemoattractant chemokine (CC motif) ligand-2 production was significantly ameliorated by Treg adoptive transfer in lung homogenates, accompanied by reduced accumulation of bone-marrow derived fibrocytes. Genetic ablation of IL-10 abrogated the ameliorating effect of Tregs on pulmonary fibrosis. Finally, splenectomy on day 0 after a BLM challenge significantly ameliorated lung fibrosis, whereas splenectomy on day 14 had no effect. CONCLUSIONS: These findings warrant further investigations to develop a cell-based therapy using Tregs for treating IPF.

DOI： 10.1186/s12931-018-0783-2

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記述言語：英語  

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4CD25FoxP3 regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis.C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully caut

DOI： 10.1186/s12931-018-0783-2

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter

DOI： 10.2169/internalmedicine.9331-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with a worse prognosis than some types of cancer. In patients with IPF, lung cancer is critical because of the associated high mortality rate from its progression and fatal complications from anticancer treatments. Therefore, preventing lung cancer in patients with IPF is primordial. Pirfenidone is an anti-fibrotic agent that reduces the decline in forced vital capacity. This study aimed to assess the effect of pirfenidone in the development of lung cancer in patients with IPF. Methods: Data from 261 patients with IPF with and without pirfenidone were retrospectively reviewed, and the incidence of lung cancer was analyzed. Results: In the pirfenidone group, the incidence of lung cancer was significantly lower than in the non-pirfenidone group (2.4% vs. 22.0%, P &lt
0.0001). Multivariate Cox proportional hazards regression analysis demonstrated that pirfenidone decreased the risk of lung cancer (hazard ratio, 0.11
95% confidence interval, 0.03 to 0.46
P = 0.003), whereas coexisting emphysema increased the incidence of lung cancer (hazard ratio, 3.22
95% confidence interval, 1.35 to 7.70
P = 0.009). Conclusions: Pirfenidone might correlate with a decreased risk of lung cancer in patients with IPF. However, no definite conclusion can be drawn from this retrospective study, and a multicenter, prospective cohort study is still warranted to confirm the effect of pirfenidone on lung cancer in patients with IPF.

DOI： 10.1016/j.resinv.2017.09.007

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記述言語：英語  

We herein describe the case of a 67-year-old woman with advanced lung adenocarcinoma who developed interstitial lung disease (ILD) with alveolar hemorrhage induced by pembrolizumab. She received four courses of pembrolizumab therapy and achieved a partial response. She had no respiratory symptoms; however, chest radiography and computed tomography (CT) revealed ground-glass opacities (GGOs) and crazy-paving pattern. Based on findings of bloody bronchoalveolar lavage fluid and transbronchial lung biopsy samples, pembrolizumab-induced ILD with alveolar hemorrhage was diagnosed. Corticosteroid therapy rapidly improved alveolar hemorrhage and regressed GGOs on CT scan. This is the first report on ILD with alveolar hemorrhage induced by pembrolizumab.

DOI： 10.2147/OTT.S169321

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記述言語：英語  

Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from <25% to >90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

DOI： 10.2147/OTT.S168598

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記述言語：英語  

A 41-year-old woman presented complaining of cough and purpura for one month. On her first visit, a blood test demonstrated peripheral blood eosinophilia, but chest radiography showed no abnormalities. However, 2 days after the first visit, she went to the emergency room because of fever and right-sided chest pain. Contrast-enhanced computed tomography of the chest showed pulmonary embolism and air space consolidation. Thrombosis was present in the popliteal vein. Bronchoscopy revealed alveolar hemorrhage and increased eosinophils in the bronchoalveolar lavage fluid, and a skin biopsy demonstrated a perivascular eosinophilic infiltrate. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). We started steroid therapy and low-molecular-weight heparin (LMWH). The chest pain and fever disappeared, and the peripheral eosinophil count normalized. However, the thrombosis in the leg worsened. It was dramatically improved by changing from LMWH to oral rivaroxaban. The thrombogenic risk of eosinophilia should be recognized. This case suggests that oral rivaroxaban is useful when thrombosis is uncontrolled by LMWH in a patient with EGPA.

DOI： 10.1016/j.rmcr.2018.05.008

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Cyclic mechanical stretching (CMS) of the alveolar epithelium is thought to contribute to alveolar epithelial injury through an increase in oxidative stress. The aim of this study was to investigate the mechanisms of CMS induced oxidative stress in alveolar epithelial cells (AECs). A549 cells were subjected to CMS, and the levels of 8-isoprostane and 3-nytrotyrosine were measured. Twenty-four hours of CMS induced a significant increase in the levels of 8-isoprostane and 3-nytrotyrosine. Although CMS did not increase the xanthine oxidase activity or the mitochondrial production of reactive oxygen species, it upregulated the expression of nicotine adenine dinucleotide phosphate oxidase (NOX) 2, 4, 5 and DUOX2. The NOX inhibitors DPI and GKT137831 significantly attenuated CMS-induced oxidative stress. Furthermore, the measurement of annexin V/propidium iodide by flow cytometry showed that CMS induced late-phase apoptosis/necrosis, which was also attenuated by both DPI and GKT137831. These data suggest that CMS mainly induces oxidative stress, which may lead to cell injury by activating NOX in AECs.

DOI： 10.1016/j.resp.2017.04.007

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担当区分：責任著者   記述言語：英語  

Nivolumab, a monoclonal antibody targeting the PD-1, has recently been used as a standard treatment for lung cancer, melanoma and renal cell carcinoma. We herein report the case of a patient undergoing treatment for non-small cell lung cancer (NSCLC) who developed interstitial pneumonia which featured nivolumab-induced granuloma formation. An 82-year-old male patient with NSCLC was initially treated with radiation therapy and chemotherapy. Five years later, however, he developed metastatic carcinoma in a hilar lymph node accompanied by ground glass opacity (GGO), suggesting tumor cell invasion. Treatment with nivolumab was initiated. At 21 days after the first dose of nivolumab, he complained of cough and dyspnea. Chest computed tomography scans demonstrated tumor progression and newly formed GGO in the area surrounding the primary tumor. Fibrosing active alveolitis with granuloma formation and organizing pneumonia findings were observed in the pathological examination of a transbronchial lung biopsy (TBLB) specimen. No malignant cells were found in TBLB. A bacteriological analysis of cultures, a PCR, and special staining did not reveal any infections. The patient's pneumonitis improved after treatment with systemic corticosteroids. Granuloma-forming interstitial pneumonia may be a feature of nivolumab-associated pneumonitis.

DOI： 10.1007/s13691-017-0291-0

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記述言語：英語  

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-β1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-β1 treatment down-regulated XPLN

DOI： 10.1016/j.pupt.2017.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extra cellular matrix, whose expression is regulated by transforming growth factor (TGF)-beta 1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-beta 1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-beta 1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration dependent manner, and TGF-beta 1-induced SPARC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated SPARC expression. In conclusion, this is the first study describing the involvement of XPLN in the regulation of SPARC. These findings may help uncover the regulatory mechanisms of the mTORC2-SPARC axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2017.03.003

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MATTIOLI 1885  

Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) was recently proposed as an entity to be included among rare idiopathic interstitial pneumonias (IIPs). However, the cause, clinical features and prognosis of this rare entity have not been elucidated. Objectives: We aimed to examine the clinical features, outcomes and prognostic factors for IPPFE in comparison to those of idiopathic pulmonary fibrosis (IPF). Methods: We retrospectively analyzed 20 patients with IPPFE and 71 with IPF. We compared clinical features, blood examination data, and respiratory functions at the time of diagnosis. Results: The IPPFE group had a significantly lower body mass index (BMI), percent forced vital capacity (% FVC), total lung capacity (% TLC) and expiratory reserve volume (% ERV), as well as a higher residual volume to TLC (RV/TLC) ratio than the IPF group. The annual FVC changes in the IPPFE group (-326ml/year) were significantly larger than those in the IPF group (-142ml/year). Survival was significantly poorer in the IPPFE than in the IPF group (P = 0.021). BMI and the partial pressure of oxygen in arterial blood (PaO2) were significantly related to the outcome of IPPFE. Conclusions: Our present results indicate the prognosis of IPPFE patients to be poorer than that of IPF patients. We advocate that BMI and arterial blood PaO2 be determined at the first visit as these parameters are closely related to patients' outcomes. Prospective evaluation of IPPFE starting in the subclinical phase is necessary to assure that appropriate measures are taken before progression.

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Context: CC chemokine ligand 18 (CCL18) is suggested to play a role in the development of pulmonary fibrosis. Macrophages are thought to be the main source of CCL18, and the effect of pirfenidone, an anti-fibrotic agent for idiopathic pulmonary fibrosis, on the expression of CCL18 in macrophages warrants investigation.Objective: The purpose of this study was to investigate the effect of pirfenidone on the expression of CCL18 in macrophages.Materials and methods: U937 cells were differentiated into macrophages by phorbol myristate acetate and then stimulated with recombinant IL-4 to induce the production of CCL18. The cells were treated with pirfenidone, and the mRNA and protein levels for CCL18 were measured by a reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The effects of pirfenidone on the IL-4 receptor (IL-4R) expression and STAT6 activation were investigated and on the JAK kinase activity were measured using the Z-LYTE kinase assay.Results: Pirfenidone significantly suppressed the expression of CCL18 when the cells were treated with concentrations of 50-250g/mL. Pirfenidone did not affect the expression of the IL-4R components. The selective STAT6 inhibitor AS1517499 suppressed CCL18 expression. Both AS1517499 and pirfenidone suppressed STAT6 phosphorylation (p&lt;.05), although the effect of pirfenidone was less marked than that of AS1517499. The Z-LYTE kinase assay showed a reduction in the activities of JAK1, JAK3 and TYK2 by pirfenidone.Conclusion: Pirfenidone suppresses CCL18 expression in macrophages and this effect is thought to be attributed partly to the inhibition of STAT6 phosphorylation.

DOI： 10.1080/08923973.2016.1247852

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiat

DOI： 10.1093/jjco/hyw043

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Dove Medical Press Ltd.  

Background: COPD is concomitantly present in ~30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD. Patients and methods: Overall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age- and sex-matched control patients with an LV ejection fraction of ≥50% were enrolled. Results: The mean age of the patients was 74.4±10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e') and the proportion of patients with high E/e' (defined as E/e' ≥ 15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009
11.3% vs 4.3%, P=0.046). E/e' was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e' (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13-15.89, P=0.001 and OR 6.00, 95% CI 2.08-17.35, P=0.001, respectively). Conclusion: Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.

DOI： 10.2147/COPD.S101082

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記述言語：日本語   出版者・発行元：(公財)日本感染症医薬品協会  

菌の増殖速度、培養上清による気道上皮細胞への傷害性、トータルプロテアーゼ(TP)、ピオシアニン(PC)産生量、バイオフィルム(BF)形成能、遊走アッセイ(MA)、病原因子の遺伝子発現への影響について検討した。クラリスロマイシン(CAM)長期服用中の慢性気道感染症患者より分離された緑膿菌(Pa)11株、CAM未投与患者から分離されたPa2株(ムコイド型)、標準株としてPa P.aeruginosa PAO1の合計14株を対象とした。増殖速度はCAM投与菌群ではCAM未投与菌群と比べ増殖速度は緩徐な傾向であった。CAM投与菌の培養上清による肺胞上皮細胞への傷害性はCAM投与菌群においてCAM未投与菌群と比べ低かった。TPアッセイはCAM投与菌11株中7株でTPが非産生、CAM未投与菌では2株中2株ともTPを産生し、CAM投与菌ではTP産生株が少ない傾向にあった。PC産生量はCAM投与菌群ではCAM未投与菌群と比べ低い傾向であった。CAM投与菌群とCAM未投与菌群間でBF形成に有意差はなかったがCAM投与菌では菌株間でBF形成にばらつきが認められた。MAについて遊走は両群間に差は認められなかった。病原因子の遺伝子発現への影響は、CAM投与菌11株中4株でQS関連遺伝子であるLasI、rhlI遺伝子の発現を認めなかったのに対し、CAM未投与菌では2株中2株ともに発現を認めた。aprA、exoS、exoT、exoYでは両群間に差を認めなかった。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：DOVE MEDICAL PRESS LTD  

Background: COPD is concomitantly present in similar to 30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD.
Patients and methods: Overall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age-and sex-matched control patients with an LV ejection fraction of &gt;= 50% were enrolled.
Results: The mean age of the patients was 74.4 +/- 10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e') and the proportion of patients with high E/e' (defined as E/e' &gt;= 15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009; 11.3% vs 4.3%, P= 0.046). E/e' was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e' (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13-15.89, P= 0.001 and OR 6.00, 95% CI 2.08-17.35, P= 0.001, respectively).
Conclusion: Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.

DOI： 10.2147/COPD.S101082

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MATTIOLI 1885  

Background and objective: There is growing evidence for anti-inflammatory activities of macrolides in chronic respiratory diseases, such as diffuse panbronchiolitis, cystic fibrosis, or chronic bronchitis. The long-term effect of macrolides in idiopathic pulmonary fibrosis (IPF) is unknown. This study was aimed to investigate the effect of macrolide therapy on the frequency of acute exacerbation (AE) and the mortality in IPF. Methods: A total 52 IPF patients who were treated by combination of conventional agents with or without macrolides were retrospectively reviewed. The primary endpoint was the incidence of AE in IPF patients. We also observed survival rate after the treatment with or without macrolides. Results: AE was observed in 4 of 29 cases (13.8%) treated with macrolides and 8 of 23 cases (34.8%) treated without macrolides, respectively during 36 months. AE free survival rate of macrolide group was significantly better than that of non-macrolide group (logrank p=0.027). Survival rate of IPF patients with macrolide therapy was significantly better than that of patients without macrolide therapy (p=0.047). Conclusion: Our results indicate the potential beneficial efficacy of macrolide therapy combined with oral corticosteroids, immunosuppressive or anti-fibrotic agents in IPF.

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記述言語：英語  

DOI： 10.1007/s13691-014-0205-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a high mortality rate. Signalling pathways activated by several tyrosine kinase receptors are known to be involved in lung fibrosis, and this knowledge has led to the development of the triple tyrosine kinase inhibitor nintedanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), for the treatment of IPF. Pulmonary surfactant protein D (SP-D), an important biomarker of IPF, reportedly attenuates bleomycin-induced pulmonary fibrosis in mice. In this study, we investigated whether nintedanib modulates SP-D expression in human lung epithelial (A549) cells using quantitative real-time reverse transcriptase polymerase chain reaction and western blotting. To investigate the mechanisms underlying the effects of nintedanib, we evaluated the phosphorylation of c-Jun N-terminal kinase (JNK) and its downstream target c-Jun. The effect of the JNK inhibitor SP600125 on c-Jun phosphorylation was also tested. Activation of activator protein-1 (AP-1) was examined using an enzyme-linked immunosorbent assay-based test, and cell proliferation assays were performed to estimate the effect of nintedanib on cell proliferation. Furthermore, we treated mice with nintedanib to examine its in vivo effect on SP-D levels in lungs. These experiments showed that nintedanib up-regulated SP-D messenger RNA expression id a dose-dependent manner at concentrations up to 5 mu M, with significant SP-D induction observed at concentrations of 3 mu M and 5 mu M, in comparison with that observed in vehicle controls. Nintedanib stimulated a rapid increase in phosphorylated JNK in A549 cells within 30 min of treatment and stimulated c-Jun phosphorylation, which was inhibited by the JNK inhibitor SP600125. Additionally, nintedanib was found to activate AP-1. A549 cell proliferation was not affected by nintedanib at any of the tested concentrations. Moreover, blocking FGFR, PDGFR, and VEGFR function did not affect nintedanib-induced SP-D expression, suggesting that nintedanib mediates its effects through a mechanism that is distinct from its known role as a tyrosine kinase inhibitor. Nintedanib is also reported to inhibit Src kinase although pre-treatment of cells with a Src kinase inhibitor had no effect on nintedanib-induced SP-D expression. Increased expression of SFTPD mRNA and SP-D protein in the lungs of nintedanib-treated mice was also observed. In this work, we demonstrated that nintedanib up-regulated SP-D expression in A549 cells via the JNK-AP-1 pathway and did not affect cell proliferation. This is the first report describing SP-D induction by nintedanib. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.pupt.2015.03.001

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1242/dev.115576

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Bone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent
however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice.Methods: Bleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated.Results: Pirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice (P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone (P = 0.0003 and P &lt
0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro.Conclusions: Pirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo, and fibrocyte migration was inhibited by pirfenidone in vitro. Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone. © 2014 Inomata et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1465-9921-15-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

Background: Combined pulmonary fibrosis and emphysema (CPFE) patients may be at significantly increased risk of lung cancer compared with either isolated emphysema or pulmonary fibrosis patients. Acute exacerbation (AE) of interstitial lung disease caused by anticancer treatment is the most common lethal complication in Japanese lung cancer patients. Nevertheless, the clinical significance of CPFE compared with isolated idiopathic interstitial pneumonias (IIPs) in patients with lung cancer is not well understood.
Methods: A total of 1536 patients with lung cancer at Nippon Medical School Hospital between March 1998 and October 2011 were retrospectively reviewed. Patients with IIPs were categorized into two groups: (i) CPFE; IIP patients with definite emphysema and (ii) non-CPFE; isolated IIP patients without definite emphysema. The clinical features, anti-cancer treatments and outcomes of the CPFE group were compared with those of the non-CPFE group.
Results: CPFE and isolated IIPs were identified in 88 (5.7%) and 63 (4.1%) patients respectively, with lung cancer. AE associated with initial treatment occurred in 22 (25.0%) patients in the CPFE group and in 8 (12.7%) patients in the non-CPFE group, irrespective of treatment modality. Median overall survival (OS) of the CPFE group was 23.7 months and that of the non-CPFE group was 20.3 months (P = 0.627). Chemotherapy was performed in a total of 83 patients. AE associated with chemotherapy for advanced lung cancer occurred in 6 (13.6%) patients in the CPFE group and 5 (12.8%) patients in the non-CPFE group. Median OS of the CPFE group was 14.9 months and that of the non-CPFE group was 21.6 months (P = 0.679).
Conclusion: CPFE was not an independent risk factor for AE and was not an independent prognosis factor in lung cancer patients with IIPs. Therefore, great care must be exercised with CPFE as well as IIP patients when performing anticancer treatment for patients with lung cancer. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2014.05.016

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Bone marrow-derived fibrocytes reportedly play important roles in the pathogenesis of idiopathic pulmonary fibrosis. Pirfenidone is an anti-fibrotic agent; however, its effects on fibrocytes have not been investigated. The aim of this study was to investigate whether pirfenidone inhibits fibrocyte pool size in the lungs of bleomycin-treated mice.
Methods: Bleomycin (100 mg/kg) was infused with osmotic pumps into C57BL/6 mice, and pirfenidone (300 mg/kg/day) was orally administered daily for 2 wk. The lungs were removed, and single-cell suspensions were subjected to fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes, which were defined as CD45 and collagen-I double-positive cells. Immunohistochemistry was performed on the lung specimens to quantify fibrocytes. Chemokines in the lung digests were measured with enzyme-linked immunosorbent assay. The effect of pirfenidone on alveolar macrophages was evaluated with bronchoalveolar lavage (BAL). In a therapeutic setting, pirfenidone administration was initiated 10 days after bleomycin treatment. For chemotaxis assay, lung fibrocytes were isolated with immunomagnetic selection (CD45-positive mesenchymal cells) after culture and allowed to migrate toward chemokines in the presence or absence of pirfenidone. Moreover, the effect of pirfenidone on the expression of chemokine receptors on fibrocytes was evaluated.
Results: Pirfenidone significantly ameliorated bleomycin-induced pulmonary fibrosis as assessed with quantitative histology and collagen measurement. Fibrocyte pool size in bleomycin-treated mice lungs was attenuated from 26.5% to 13.7% by pirfenidone on FACS analysis. This outcome was also observed in a therapeutic setting. Immunohistochemistry revealed that fibrocytes were significantly decreased by pirfenidone administration compared with those in bleomycin-treated mice (P = 0.0097). Increased chemokine (CC motif) ligand-2 (CCL2) and CCL12 production in bleomycin-treated mouse lungs was significantly attenuated by pirfenidone (P=0.0003 and P &lt; 0.0001, respectively). Pirfenidone also attenuated macrophage counts stimulated by bleomycin in BAL fluid. Fibrocyte migration toward CCL2 and chemokine (CC motif) receptor-2 expression on fibrocytes was significantly inhibited by pirfenidone in vitro.
Conclusions: Pirfenidone attenuated the fibrocyte pool size in bleomycin-treated mouse lungs via attenuation of CCL2 and CCL12 production in vivo, and fibrocyte migration was inhibited by pirfenidone in vitro. Fibrocyte inhibition is considered a mechanism of anti-fibrotic action of pirfenidone.

DOI： 10.1186/1465-9921-15-16

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MATTIOLI 1885  

Background and objectives: Acute eosinophilic pneumonia (AEP) is a very rare condition, with only one paper published so far discussing histopathological findings at surgical biopsy. In that paper, AEP is considered to be an acute and proliferative stage of DAD accompanied by eosinophilia. However, acute respiratory distress syndrome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis, which, unlike AEP are mostly life-threatening diseases, also exhibit DAD. AEP also presents with severe hypoxia but rapidly improves on treatment with corticosteroids alone, without subsequent fibrosis. In contrast, the other above-mentioned diseases with the same histopathology show greatly different clinical courses. The reasons for these differences remain unclear. Methods: Here we investigated the histopathology of AEP in 2 surgical lung biopsy and 14 transbronchial lung biopsy cases. Additionally, we determined the presence or absence of different phases of DAD by histopathology in these AEP cases. Results and Conclusion: Characteristic histopathological findings of AEP consist of alveolar edema with infiltration of eosinophils and lymphocytes and edema of perivascular area and interlobular septa. The alveolar spaces showed fibrinous exudates. There were no hyaline membranes or massive intraluminal fibrosis. These histopathological findings of interstitial edema and fluid exudates are consistent with radiological findings of lung edema and can explain the rapid and complete improvement. Because AEP does not exhibit lung fibrosis histopathologically, it should not to be included in DAD which is associated with lung fibrosis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

A 76-year-old female with advanced renal cell carcinoma had been treated with everolimus for 3 months. She visited our hospital because of a cough and fever lasting a few days. Chest X-rays showed bilateral infiltrative shadows, and a chest computed tomography scan showed homogeneous ground-glass opacities with mosaic patterns, especially in the apical region. The laboratory results revealed a decreased white blood cell count with lymphocytopenia and high levels of lactate dehydrogenase, C-reactive protein and KL-6. Pneumonitis was suspected and, therefore, everolimus therapy was interrupted. At that time, the pneumonitis was thought to be drug-induced interstitial lung disease. However, it was not possible to rule out pneumocystis pneumonia, because the patient was immunocompromised and the computed tomography findings suggested the possibility of pneumocystis pneumonia. The pneumonitis progressed rapidly and the patient developed respiratory failure, so we performed bronchoalveolar lavage to make a definitive diagnosis, and simultaneously started treatment with prednisolone and trimethoprimsulfamethoxazole to cover both interstitial lung disease and pneumocystis pneumonia. A polymerase chain reaction assay of the bronchoalveolar lavage fluid was positive for Pneumocystis carinii DNA, and the serum level of -d-glucan was significantly elevated. Thus, the patient was diagnosed with pneumocystis pneumonia, which was cured by the treatment. Interstitial lung disease is a major adverse drug reaction associated with everolimus, and interstitial lung disease is the first condition suspected when a patient presents with pneumonitis during everolimus therapy. Pneumocystis pneumonia associated with everolimus therapy is rare, but our experience suggests that pneumocystis pneumonia should be considered as a differential diagnosis when pneumonitis is encountered in patients receiving everolimus therapy.

DOI： 10.1093/jjco/hyt019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

We experienced a case of interstitial lung disease (ILD) that occurred one year after the start of everolimus therapy for renal cell carcinoma. The pathological features included interstitial pneumonia with granuloma formation. Everolimus is known to cause ILD; however, its pathology is unclear. Granuloma-forming interstitial pneumonia associated with everolimus is uncommon, although it may be one of the pathological patterns associated with everolimus-induced ILD. This is a slow-onset case of everolimus-induced ILD in a patient with renal cell carcinoma. Physicians should thus be aware of the potential for the development of ILD at any time during the administration of everolimus therapy.

DOI： 10.2169/internalmedicine.52.8588

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記述言語：英語   出版者・発行元：SPRINGER JAPAN KK  

Molecular targeted drugs have become the mainstream for cancer therapy, and they have contributed to improving the outcome for cancer patients. On the other hand, molecular targeted drugs are associated with a variety of adverse drug reactions. Drug-induced interstitial lung disease (DILD) is a typical adverse drug reaction that has been an important problem with regard to safety management during cancer treatment. In the past, there was a lack of detailed and accurate epidemiological data about DILD. However, most of the molecular targeted drugs have been subject to all-case post-marketing surveillance since gefitinib-induced ILD became a concern. These surveillance data present useful information about DILD, such as frequency of adverse events, mortality, and risk factors, and as a result, the epidemiological profile of DILD associated with molecular targeted drugs has become apparent during the past decade. Further, it has been considered that the principal management for DILD is early detection and cessation of the suspected cause. However, ILD associated with everolimus and temsirolimus requires unusual management; i.e., patients with asymptomatic ILD are allowed to continue treatment with everolimus or temsirolimus, and even after symptomatic ILD, both everolimus and temsirolimus are allowed to be readministered after the resolution of ILD. As a result of the collected data, a change has begun in the field of DILD associated with molecular targeted drugs. The features of DILD can differ for each drug, and clinicians should thus keep this information about DILD in mind while treating patients.

DOI： 10.1007/s10147-012-0494-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

This report presents the cases of three patients with fatal pneumonia that was highly suspected to be Pneumocystis pneumonia (PCP) based on serological diagnosis. Their chest radiographs showed bilateral pneumonia and each had presented with severe respiratory failure requiring mechanical ventilation when they arrived at the hospital. Although bronchoscopical sampling could not be performed, their chest computed tomography imaging and a marked elevation of serum KL-6 and -d-glucan levels were characteristic of Pneumocystis pneumonia. All three were found to have been treated with temozolomide after surgery for malignant glioma. Temozolomide can cause Pneumocystis pneumonia. The three patients did not receive prophylactic medication against Pneumocystis pneumonia during treatment with temozolomide, and their histories suggested that all had delayed seeking treatment. It may be difficult to diagnose Pneumocystis pneumonia because the symptoms are not specific for Pneumocystis pneumonia and they tend to be similar to those of common respiratory infectious diseases. Therefore, patients who receive temozolomide therapy have the potential to develop fatal pneumonia and should be carefully observed. The patients should also be adequately informed about Pneumocystis pneumonia, and prophylaxis against Pneumocystis pneumonia should be considered proactively before treatment with temozolomide is initiated.

DOI： 10.1093/jjco/hys058

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記述言語：日本語  

A number of anticancer drugs, especially molecularly-targeted drugs, have been developed every year. Drug-induced interstitial lung disease (DILD) is a common adverse event associated with molecularly-targeted drugs, and it is therefore important to obtain information about the DILD risks of each drug. Recently, all-case surveillance of new drugs have been carried out frequently as post-marketing surveillance. This allows one to understand the accurate status of DILD, such as its incidence rate and prognosis. The diagnosis of DILD is often difficult because there is no specific diagnostic approach. It is necessary to distinguish DILD from various other diseases including infectious disease, cancer progression, congestive heart failure, etc. Among those, respiratory infection is an important disease in the differential diagnosis of DILD, because patients receiving anticancer drugs are likely to be susceptible to infection. As for the treatment of DILD, the general rule is the discontinuation of the offending drug, and if necessary, the administration of corticosteroid is indicated. However, an exceptional treatment is required for DILD caused by mTOR inhibitor, for which we must take account of the adequate management.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aim: Recent reports suggest that polymyxin B (PMX)-immobilized fiber may have beneficial effects in idiopathic pulmonary fibrosis (IPF) with acute exacerbation (AE). High mobility group box-1 (HMGB-1) is an important pro-inflammatory mediator that contributes to acute lung inflammation. This study was aimed to investigate whether PMX treatment affects serum HMGB-1 levels and oxygenation in IPF patients with AE. Materials and Methods: Twenty IPF patients with AE were treated by PMX. PMX treatment was carried out once daily for 2 successive days. Serum HMGB-1 levels were measured before and after PMX treatment. We also monitored arterial oxygen tension (PaO(2))/inspiratory oxygen fraction (FiO(2)) (P/F) ratio. PMX fiber columns were analyzed to examine whether HMGB-1 was absorbed by PMX. Results: PMX treatment significantly improved both the serum HMGB-1 level and P/F ratio. HMGB-1 was detected in washing medium from the PMX column. Conclusion: PMX treatment may reduce serum HMGB-1 and improve oxygenation in patients with IPF with AE. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000330325

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.33.Special_S299_3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Background and objective: The histological type of intraluminal fibrosis is an important prognostic factor for interstitial pneumonia. We therefore examined whether transbronchial lung biopsy (TBLB) specimens are useful for predicting the clinical course and prognosis of patients with interstitial pneumonia associated with polymyositis and dermatomyositis (PM/DM), with particular attention to the different types of intraluminal fibrosis.
Methods: Twenty-five cases of interstitial pneumonia associated with PM/DM were classified according to the pattern of intraluminal fibrosis as assessed by TBLB, and the clinical course and response to treatment were compared. Interstitial fibrosis was evaluated by sequential thin-section CT scans.
Results: In 19 of 25 (76%) cases, there was sufficient intraluminal fibrosis to perform an evaluation. Intraluminal fibrosis was classified as bud (polyp) type or mural incorporation type (either alone or mixed with bud type). The bud type was seen in five cases and these improved following treatment with corticosteroids only. The mural incorporation type was seen in 14 cases. In 11 of these 14 cases, progressive long-term fibrosis developed and four cases were fatal, in spite of corticosteroid and immunosuppressive therapy. The response to drugs (P &lt; 0.01) and survival (P &lt; 0.05) were significantly greater in patients with bud-type than mural incorporation-type intraluminal fibrosis.
Conclusions: Classification of the pattern of intraluminal fibrosis as assessed by TBLB is useful for predicting the response to treatment, clinical course and prognosis of interstitial pneumonia associated with PM/DM.

DOI： 10.1111/j.1440-1843.2008.01363.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Background Pneumocystis jiroveci pneumonia (PCP) is a potentially fatal complication in interstitial pneumonia patients receiving glucocorticoid therapy. Prophylaxis of PCP during glucocorticoid therapy is an important issue in the treatment of interstitial pneumonia.
Objective We evaluated the prophylactic effect of sulfamethoxasole-trimethoprim (TMP-SMX) in interstitial pneumonia patients receiving glucocorticoids.
Methods We retrospectively analyzed 74 interstitial pneumonia patients who received glucocorticoid therapy.
Results Seven of the 74 patients developed PCP. At the time of diagnosis of PCP, the mean duration of glucocorticoid therapy was 71 days and the mean daily dose of prednisolone was 37 mg. Among the 7 patients, the circulating CD4+ lymphocyte count was 370/mu l on average and it was over 200/mu l in 3 cases. The PCP patients showed a significant reduction of the lymphocyte count at 4 weeks after initiation of steroid therapy. None of the patients who received prophylactic TMP-SMX therapy developed PCP even if the CD4+ lymphocyte count was less than 200/mu l.
Conclusion Interstitial pneumonia patients receiving glucocorticoid therapy can benefit from TMP-SMX prophylaxis against PCP. Development of PCP cannot be ruled out in patients with a CD4+ lymphocyte count of greater than 200/mu l.

DOI： 10.2169/internalmedicine.47.0402

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Low-dose, long-term macrolide therapy has been shown to be effective for the treatment of diffuse paribronchiolitis (DPB) and similar disorders in terms of the presence of airway mucus hypersecretion such as bronchiectasis, chronic bronchitis and sinobronchial syndrome. However, there are some patients, especially advanced cases, whose volume of sputum does not decrease sufficiently with macrolide therapy. These patients suffer from copious expectoration. There is currently no effective treatment, and an effective therapy is therefore urgently required. The aim of this study was to clarify whether or not the inhalation of tiotropium improves the symptoms in these cases. Methods Tiotropium (18 mu g/day) was administered to patients with DPB and similar disorders with airway mucus hypersecretion who did not respond to macrolide. The symptoms were evaluated by a visual analog scale (VAS) prior to and at 1 and 3 months after tiotropium administration. Radiological and pulmonary function tests were also performed to evaluate the effects of tiotropium. Results Thirteen patients (DPB 5, sinobronchial syndrome 5, bronchiectasis 3) were enrolled. The VAS scores were dramatically improved after the introduction of tiotropium. FEV1 was significantly improved after 3 months of treatment with tiotropium. In contrast, the radiological findings remained unchanged. Conclusion Tiotropium improved the symptoms of cough, sputum and breathlessness in the macrolide-resistant cases of DPB or similar disorders. These beneficial effects might be due to the suppression of airway secretion through the anticholinergic effect of tiotropium on the submucosal gland, however, the long-term efficiency of this treatment still needs to be further assessed.

DOI： 10.2169/internalmedicine.47.0568

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 64-year-old woman with rheumatoid arthritis and treated with bucillamine presented with a productive cough. No obvious infiltration was detected in chest radiography, but CT revealed patchy ground glass opacities in bilateral lung fields. Her serum KL-6 level was elevated and transbronchial lung biopsy showed interstitial pneumonia. Drug lymphocyte stimulation test (DLST) for bucillamine was negative for blood lymphocytes, but positive for bronchoalveolar lavage (BAL) lymphocytes. The pneumonitis improved after the cessation of bucillamine. We therefore made a diagnosis of bucillamine-induced interstitial pneumonia. DLST with BAL lymphocytes is thus suggested to be useful for such diagnoses.

DOI： 10.2169/internalmedicine.46.0139

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記述言語：日本語  

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective This study was aimed to investigate the effect of polymyxin B-immobilized fiber column (PMX) hemoperfusion treatment on the acute exacerbation of idiopathic pulmonary fibrosis (IPF).
Patients and Methods Six patients with a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) who developed acute exacerbation were included in this study. Although five of six patients were treated with high-dose corticosteroid therapy, mechanical ventilation was necessary for all six patients due to severe respiratory failure. Blood endotoxin levels were undetectable in all patients. PMX treatment was performed on these six patients.
Results In four of six patients, alveolar-arterial difference of oxygen (AaDO(2)), serum KL-6 and lactate dehydrogenase (LDH) were improved after PMX treatment. These four patients were successfully weaned from mechanical ventilation and survived more than 30 days after the initial PMX treatment.
Conclusion These data suggest a potential beneficial effect of PMX treatment on acute exacerbation of IPF.

DOI： 10.2169/internalmedicine.45.6018

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

85歳男.四肢脱力感,歩行困難を主訴とした.79歳より慢性閉塞性肺疾患(COPD)の経過観察をされ,81歳より進行膀胱癌(移行上皮癌)でフルオロウラシル製剤内服を継続していた.入院時検査にて低カリウム血症,胸部単純X線・CT各所見にて両肺に高度な気腫性変化をび漫性に認め,左肺は巨大肺嚢胞および胸水の貯留を認めた.また,頭部CTより小脳虫部に腫瘤病変を認めた.胸水は第2病日の試験穿刺より漏出性胸水と診断し,穿刺後SpO2が低下し緊張性気胸様状態となった.緊急胸腔ドレナージにて一時的に改善したが,意識状態が悪化し第3病日目に死亡した.剖検の結果,肺気腫,膀胱癌の多発転移,癌性リンパ管症,右腎結核,右心拡張・左室肥大であった.なお,四肢脱力感は低カリウム血症に因るものと推察した

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

The authors investigated the effects of inhalation of diesel exhaust ( DE) on murine mycobacterial infection in vivo. Eight-week-old female BALB/c mice were exposed to DE ( 3 mg/m(3) of diesel exhaust particles [DEPs]) for 1 month, 2 months, or 6 months ( for 7 hours a day, 5 days a week). Control mice were housed in a clean room for the same periods. On the day following the last DE exposure, control mice and DE-exposed mice were aerially infected with Mycobacterium tuberculosis ( 1 x 10(6) colony-forming units (CFU), Kurono strain). At 7 weeks after mycobacterial infection, the authors examined the lung tissues for histopathological changes and performed reverse transcriptase - polymerase chain reaction (RT-PCR) to measure the messenger RNA ( mRNA) expression of several proinflammatory cytokines and inducible nitric oxide synthase ( iNOS). Then, the homogenates of lungs and spleens were cultured on 1% (v/v) Ogawa's egg slant medium, and after a 4-week incubation period at 37 degrees C, colonies on the medium were counted. After 1 month of DE exposure, the mycobacterial infection had slightly ameliorated. After 2 months of DE exposure, the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-12p40, interferon (IFN)-gamma, and iNOS mRNAs were slightly increased. However, after 6 months of DE exposure, the expression levels of IL-1 beta, IL-12p40, IFN-gamma, and iNOS mRNAs were decreased, and the infection as measured by increased lung burden ( CFU) actually increased. These results indicate that long-term DE exposure may increase pulmonary mycobacterial burden.

DOI： 10.1080/01902140590918786

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Fine particles derived from diesel engines, diesel exhaust particles (DEP), have been shown to augment gene expression of several inflammatory cytokines in human airway epithelial cells in vitro. However, it remains unclear whether or not DEP have any effect on the expression and production of eotaxin, an important chemokine involved in eosinophil recruitment into the airways. We studied the effects of DEP by using a conventional suspended DEP and by a recently established in vitro cell exposure system to diesel exhaust (Abe S, Takizawa H, Sugawara I, and Kudoh S, Am J Respir Cell Mol Biol 22: 296 - 303, 2000). DEP showed a dose-dependent stimulatory effect on eotaxin production by normal human peripheral airway epithelial cells as well as by bronchial epithelial cell line BET-1A as assessed by specific ELISA. mRNA levels increased by DEP were shown by RT-PCR. DEP showed an additive effect on IL-13-stimulated eotaxin expression. DEP induced NF-kappaB activation by EMSA as previously reported but did not induce signal transducer and activator of transcription ( STAT) 6 activation according to Western blot analysis. Finally, antioxidant agents (N-acetyl cysteine and pyrrolidine dithiocarbamate), which inhibited NF-kappaB activation but failed to affect STAT6 activation, almost completely attenuated DEP-induced eotaxin production, whereas these agents failed to attenuate IL-13-induced eotaxin production. These findings suggested that DEP stimulated eotaxin gene expression via NF-kappaB-dependent, but STAT6-independent, pathways.

DOI： 10.1152/ajplung.00358.2002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Bleomycin (BLM) is known to induce lung inflammation and subsequent fibrosis. Endothelial cells have been reported to play an important role, producing cytokines and adhesion molecules during the inflammatory process in pulmonary fibrosis. To examine the effects of BLM on endothelial cells, we investigated the expression profiles of various cytokines and adhesion molecules produced by endothelial cells stimulated with BLM. Increased expressions of interleukin-8 and monocyte chemoattractant protein-1 measured as protein as well as mRNA by human umbilical vein endothelial cells (HUVECs) were detected after exposure to BLM. Similarly, increased expressions of E-selectin and intercellular adhesion molecule-3 were detected both at the protein and mRNA levels. Under these conditions, a small but significant decrease of [H-3]thymidine uptake was detected. These findings indicate that HUVEC were stimulated to secrete cytokines and express adhesion molecules in the presence of low concentrations of BLM which have a mildly inhibitory effect on cellular proliferation. (C) 2002 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0008-8749(02)00599-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

The authors investigated the effect of diesel exhaust (DE) on cytokine expression in marine lung tissues. BALB/c mice were exposed to DE for 1 month at different dose levels of DE (low dose: diesel exhaust particles [DEP] 100 mug/m(3) high dose: 3 mg/m(3)). After exposure, the authors examined mRNA expression of cytokines (tumor nocrosis factor alpha [TFN-alpha], Interleukin [IL]-1beta, IL-4, IL-6, IL-10, IL-12p40, and interferon gamma [IFN-gamma] and inducible nitric oxide synthase (iNOS) in the lung, and also measured the secretion of TNF-alpha and IL-10 protein by alveolar macrophages (AM). The mRNA expression Levels of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-12p40, IFN-gamma) and iNOS, which are important for host defense, were suppressed significantly. However the IL-10 mRNA level was increased by DE exposure. The IL-4 mRNA level was increased by low-dose DE exposure but suppressed by high-dose DE exposure. TNF-alpha and IL-10 secretion by AM paralleled mRNA expression. Chronic inhalation of DE affects cytokine expression in marine lung. These results suggest that DE alters immunological responses in the lung and may increase susceptibility to pathogens, and that increased IL-4 expression by low-dose DE exposure may induce allergic reaction such as asthma.

DOI： 10.1080/01902140290096764

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

To investigate the effects of diesel exhaust particles (DEP) and mycobacterial injection on macrophages, we examined protein and mRNA expression levels of various cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-12, and IL-18 in BALB/c mouse alveolar macrophages (AM) and a macrophage cell line (RAW264.7) after in vitro stimulation with diesel exhaust (DE), with and without Mycobacterium bovis bacillus Calmette-Guerin (BCG). The cells were exposed to DE freshly generated in an in vitro system. When AM were exposed to DE (mean DEP exposure level, 300 mug/m(3)), the levels of TNF-alpha and IL-12 decreased significantly (by 51% to 61% for TNF-alpha and by 69% to 78% for IL-12), whereas those of IL-1beta and IL-18 remained unchanged. When AM were exposed to DE and then treated with BCG, the level of TNF-alpha decreased In 45% to 71%, whereas the level of IL-1beta increased by 154%, compared with AM treated with BCG alone. Similarly, RAW264.7 cells were stimulated with DF with anti without M. bovis BCG and cytokine mRNA levels examined by reverse transcriptase-polymerase chain reaction (RTPCR). Longer exposure to DE decreased TNT-alpha and IL-12 mRNA levels in the RAW264.7 cells. When the cells were exposed to DE and subsequently treated with BCG, levels of TNF-alpha, IL-1beta, and IL-12 mRNAs decreased compared with those of cells treated with BCG alone. These results show that DE exposure has complex and diverse effects on cytokine production by AM, and that longer exposure (&gt; 8 hours) may suppress cytokine production by AM in vitro. Longer exposure of DE may therefore suppress the host defense in the lung and may increase susceptibility to lung infections such as mycobacterial infection.

DOI： 10.1080/019021402753570509

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

This study was designed to determine the identity of granulomatogenic substances in Mycobacterium bovis BCG Pasteur. When heat-treated BCG Pasteur bacilli were introduced into the lungs of guinea-pigs by an inhalation exposure apparatus, pulmonary granulomas without necrosis developed. Furthermore, when four kinds of mycolates derived from M. tuberculosis Aoyama B strain were introduced into the lungs by the same method, only trehalose 6,6'-dimycolate (TDM) and methyl ketomycolate induced pulmonary granulomas without central necrosis. The pulmonary granulomas consisted of epithelioid macrophages and lymphocytes. When a mixture of TDM and anti-TDM antibody was introduced into the lungs, development of granulomatous lesions was reduced. These data indicate that TDM and methyl ketomycolate are potent granulomatogenic reagents.

DOI： 10.1099/0022-1317-51-2-131

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記述言語：日本語  

CiNii Books

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記述言語：日本語  

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その他リンク： http://search.jamas.or.jp/link/ui/2013153828

記述言語：日本語  

肺の線維化は種々の疾患で起こるが、現在最も重篤な疾患は特発性肺線維症(Idiopathic Pulmonary Fibrosis:IPF)である。肺の線維化病態には線維芽細胞、筋線維芽細胞が中心的役割を演じているが、それらの細胞の活性にTh1/Th2サイトカインがかかわっていることが知られている。実際にTh1サイトカインであるインターフェロンγ(IFN-γ)は線維芽細胞のコラーゲン産生を抑制することが確認されており、さらにIPFの肺組織におけるTh1/Th2バランスはTh2優位であることも報告されている。そのような背景をもとに、IPFに対するIFN-γ療法について欧米を中心に臨床試験が行われ、今後のIPFの治療戦略として大きな関心が寄せられた。しかし、IFN-γの有効性が期待されるのは%FVCの低下が比較的軽度の患者群であり、現在も%FVC≧55%の患者に限って大規模臨床試験が続けられている。(著者抄録)

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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J-GLOBAL

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記述言語：英語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：日本サルコイドーシス  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

49歳男性。12月下旬より乾性咳嗽が出現し、1月上旬より発熱、呼吸困難を自覚したため前医を受診し、レボフロキサシンを処方されるも改善せず、精査加療目的に当院へ入院となった。所見では胸部単純X線およびCTで両側肺野にすりガラス陰影や小葉中心性粒状影が認められた。非定型肺炎と考え、レボフロキサシンを継続投与することで、症状は改善傾向を認めたが、一方で臨床経過や検査結果を踏まえて、過敏性肺炎も疑われ、退院の際には自宅の清掃や羽毛布団の買い替えを行うことを伝えた。そして退院後、入院時に提出していた抗トリコスポロン・アサヒ抗体陽性が判明し、また自宅帰宅後に発熱、乾性咳嗽の再燃を認めたことから、本症例は夏季以外に発症した夏型過敏性肺炎と診断された。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J04260&link_issn=&doc_id=20220831380009&doc_link_id=10.1272%2Fmanms.18.289&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.18.289&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本結核病学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本結核病学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本結核病学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

50歳女性。重症筋無力症・胸腺腫の診断で胸腺摘出術後、放射線化学療法、およびステロイド、免疫抑制剤治療中であった。診断から約5年後、湿性咳嗽と、胸部造影CTでは両側肺野に小葉中心性の粒状影の出現を認めた。HLA-B54遺伝子は陰性であり、低γグロブリン血症、B細胞数低下を伴っている点がびまん性汎細気管支炎(diffuse panbronchiolitis:DPB)と合致しなかったため、DPB様の病態を合併したGood症候群と診断した。本症例のようにマクロライド療法無効な症例は稀であるため報告する。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)先端医学社  

内因性のmTORC2 inhibitorであるExchange factor found in platelets, leukemic and neuronal tissues(XPLN)の作用を通じてmTORC2と肺線維化病態との関連を明らかにし、特発性肺線維症(IPF)の新たな治療戦略を模索することを目的とした。肺線維芽細胞として、human fetal lung fibroblast(HFL-1 cell)を使用した。Small interfering RNA(siRNA)を用いてXPLNをノックダウンし、下流に発現する分子への影響をreal-time PCRとwestern blottingを用いて検討した。またsecreted protein acidic and rich in cysteine(SPARC)の蛍光免疫染色も行った。siRNAによるXPLNのノックダウンによりSPARCの発現が増加し、mTORC2とSPARCとの関連が示された。さらに、HDAC inhibitor(HDACi)であるMS275(entinostat)とSAHA(vorinostat)を用いてHFL-1細胞におけるXPLN発現への影響について検討したところ、両HDACiは濃度依存性にHPLNの発現を有意に増加させた。siRaptorによるXPLNの発現増強はmTORC2活性化に伴いそれを抑制しようとする調節機構と考えられた。

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本結核病学会関東支部学会・日本呼吸器学会関東地方会  

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記述言語：日本語   出版者・発行元：日本サルコイドーシス  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.9077

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.6_695_4

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S316_1

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S310_2

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記述言語：日本語   出版者・発行元：日本医事新報社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2015144826

記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   出版者・発行元：じほう  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2015130043

記述言語：日本語  

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PubMed

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   出版者・発行元：文京学院大学総合研究所  

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その他リンク： http://search.jamas.or.jp/link/ui/2016337052

記述言語：日本語   出版者・発行元：文京学院大学総合研究所  

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その他リンク： http://search.jamas.or.jp/link/ui/2016337051

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本医科大学医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Web of Science

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記述言語：日本語   出版者・発行元：日本医師会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2014339120

記述言語：日本語   出版者・発行元：克誠堂出版  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2014245354

記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景. 肺癌の縦隔リンパ節転移診断には、従来よりCT、FDG-PET、縦隔鏡検査などが用いられるが、近年超音波気管支鏡ガイド下針生検(endobronchial ultrasound-guided transbronchial needle aspiration:EBUS-TBNA)の臨床応用が検討されつつある。症例. 79歳女性。両側鼠径部リンパ節腫脹を主訴に近医を受診。胸部CT上右S5結節影、両側網状粒状影、両側肺門・縦隔リンパ節腫脹を認めた。右S5結節影に対する経気管支肺生検(TBLB)にて肺腺癌と診断した。またツベルクリン反応陰性、血清ACE高値よりサルコイドーシスが疑われ、TBLBにて非乾酪性類上皮細胞肉芽腫を認め、サルコイドーシスと診断した。EBUS-TBNAによる気管分岐下リンパ節生検はclass IIであり、臨床病期cT1bN0M0、stage IAと診断し、右中葉切除術を施行した。結論. サルコイドーシス合併肺癌においては、縦隔リンパ節転移の評価に難渋するが、EBUS-TBNAによる術前評価の上手術を施行し得た1例を経験したので報告する。(著者抄録)

DOI： 10.18907/jjsre.36.3_239

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

症例は81歳男で、1年半前より間質性肺炎を指摘されていたが、胸部高分解能CTで両側肺底部に蜂巣肺を認め、特発性肺線維症(IPF)と診断した。呼吸困難が次第に増悪し、胸部X線で両側末梢側優位の網状影の他、両側中下肺野に新たなスリガラス影が出現した。また左下葉S10には既存の蜂巣肺に重なるconsolidationを認めた。IPF急性増悪と診断したが、呼吸器感染症の関与も考え、入院同日よりメチルプレドニゾロン1000mg/日のステロイド大量療法を開始し、レボフロキサシン500mg/日を併用した。第3病日に喀痰抗酸菌塗抹集菌法3+、結核菌-PCR陽性が判明し、肺結核と診断して抗結核療法を開始した。第36病日の喀痰塗抹検査で陰性化が確認され、胸部CT所見も改善したが、呼吸状態が再度悪化した。IPFの再増悪と考え、ステロイド大量療法、プレドニゾロン60mg/日を行ったが、第52病日に呼吸不全のため死亡した。

DOI： 10.1272/manms.10.111

CiNii Books

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その他リンク： https://jlc.jst.go.jp/DN/JALC/10034831600?from=CiNii

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：日本語   出版者・発行元：(株)自然科学社  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景。血管型Ehlers-Danlos症候群(vEDS)は、血管や組織の脆弱性のため、侵襲的処置に関して慎重な対応が必要である。症例。36歳男性。腹痛を主訴に近医を受診した際、多発性動脈瘤・動脈解離を指摘された。血管疾患による突然死の家族歴もあり、vEDSが疑われ紹介となった。遺伝子解析中に難治性の右気胸を2ヵ月間で計3回発症した。3回目の胸腔ドレナージは効果なく、Endobronchial Watanabe Spigot(EWS)による気管支充填術を施行したところ、エアリークは消失し、右肺拡張も得られたためドレーン抜去に成功した。皮膚線維芽細胞からのcDNAクローニングの結果、COL3A1遺伝子変異が同定され、vEDSの診断に至った。結論。組織脆弱性を理由に外科的治療を選択しにくい難治性気胸に対し、気管支充填術は有用な治療法の1つと考える。(著者抄録)

DOI： 10.18907/jjsre.35.5_506

J-GLOBAL

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記述言語：日本語  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE BV  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE BV  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.35.1_116_3

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記述言語：日本語   出版者・発行元：(一社)日本感染症学会  

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記述言語：英語  

PubMed

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

Web of Science

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：医学書院  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012272130

PubMed

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記述言語：日本語   出版者・発行元：医学書院  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012243602

記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.Special_S189_3

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.Special_S265_2

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：科学評論社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012193478

記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本感染症学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.2_198_2

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記述言語：日本語   出版者・発行元：科学評論社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012181892

記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

An 83-year-old man presented with supraclavicular and mediastinal lymph nodes swelling and elevated serum levels of neuron-specific enolase (NSE), pro-gastrin-releasing peptide (pro-GRP), and cytokeratin fragment (CYFRA). He underwent supraclavicular lymph node dissection. The pathological diagnosis was metastatic lymph node neuroendocrine carcinoma. The initial diagnosis was small cell lung carcinoma c-TxN3M0 III B with an unknown primary site, because fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) had revealed increased uptake in the neck and mediastinal lymphadenopathy, but no significant intrapulmonary uptake. However, computed tomography (CT) of the chest had detected a lesion, which was assumed to be a vessel, in the right lower lung. The patient underwent radiotherapy, and CT of the chest 1 month later revealed a partial response of the lymph nodes. However, at the same time, disease recurred in the skin adjacent to the site of supraclavicular lymph node dissection, and the lesion in the right lower lung enlarged. We suspected that this intrapulmonary lesion was the primary site. Metastasis to cervical and mediastinal lymph nodes from an unknown primary carcinoma is rare, and the primary site should be determined so that appropriate treatment can be performed. If the primary site cannot be determined with the initial examination, regular follow-up examinations with CT, magnetic resonance imaging, and FDG-PET should be performed.&lt;br&gt;

DOI： 10.1272/manms.8.162

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：ヴァン・メディカル  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2012045199

記述言語：日本語  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：科学評論社  

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その他リンク： http://search.jamas.or.jp/link/ui/2011334868

記述言語：日本語   掲載種別：会議報告等   出版者・発行元：日本気胸・嚢胞性肺疾患学会  

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記述言語：日本語   出版者・発行元：東京医学社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2011285954

記述言語：日本語   出版者・発行元：克誠堂出版  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2011253942

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)南江堂  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J00974&link_issn=&doc_id=20100114230023&doc_link_id=issn%3D0022-1961%26volume%3D105%26issue%3D1%26spage%3D127&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D105%26issue%3D1%26spage%3D127&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(株)自然科学社  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   掲載種別：会議報告等   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)先端医学社  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

37歳女。9年前に不明熱、頸部リンパ節腫脹で慢性Epstein-Barr(EB)ウイルス感染症および慢性気管支炎と診断され、その後徐々に湿性咳嗽が出現し、胸部CTで小葉中心性の粒状影を指摘された。ロキシスロマイシンで2年間は症状改善傾向を認めたが、その後徐々に増悪し、両側足趾扁平上皮癌手術目的で入院の際に精査を行った。検査所見で慢性活動性EBウイルス感染症を認め、入院後VCA-IgG、EA-IgGは徐々に上昇し、EBNA-IgGは陰性であった。生検した肺組織でEBウイルスDNA PCRが陽性であった。肺胞領域ではII型肺胞上皮の過形成、間質にリンパ球主体の炎症細胞浸潤が目立ち、肺胞腔内には壁在型の線維化を軽度認めた。比較的中枢の気管支壁にはリンパ球、好中球の浸潤を認め、慢性活動性気道炎症の所見であった。入院5ヵ月目に急性骨髄性白血病を発症し、化学療法を開始したところ、EBウイルスは検出感度以下となり、画像所見、呼吸機能、喀痰量などの自覚症状も改善した。

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

57歳男.約10年前,び漫性汎細気管支炎(DPB)と診断され,入退院を繰り返していた.マクロライド療法が無効であったため,10回目の入院時にtiotropium投与を開始したところ,喀痰量は減少し,退院1年経過後も急性増悪を起こさず病状は安定している.そこで,tiotropiumによる気道分泌抑制が,マイクロライド無効症例の病状を改善する可能性について検討した.対象は,マイクロライド療法が無効なDPB 3例,副鼻腔気管支症候群2例,気管支拡張症1例,primary ciliary dyskinesia 1例であった.その結果,tiotropiumは難治性気道感染症の咳嗽や喀痰症状を改善することが示唆された

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

31歳女性.3年前から労作時呼吸困難を呈し喘息の診断にて近医開業医で経過観察されていたが改善ないため他院を受診.胸部CTでびまん性多発性嚢胞性陰影を呈し,肺リンパ脈管筋腫症を疑われ精査目的で当院へ紹介.多クローン性高ガンマグロブリン血症,高IL-6血症,左鼠径部に最大径11mm程度の表在リンパ節腫脹を認めた.胸腔鏡下肺部分切除生検を実施.病理学的に細気管支から呼吸細気管支領域に形質細胞の著しい浸潤を認め免疫染色ではpolyclonalな染色パターンを示した.腹腔内リンパ節の著明な腫脹もあり,肺浸潤を伴う多中心性キャッスルマン病と診断した.本例の特徴は画像所見上,肺実質の著明な破壊,嚢胞形成であった.びまん性嚢胞性変化を呈する疾患として本症も考慮し,検索することが重要である(著者抄録)

CiNii Books

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(株)自然科学社  

間質性肺炎の急性増悪に対するエンドトキシン吸着療法(PMX-DHP)の効果について検討した.対象はステロイドパルス療法が無効でPMX-DHPを試みた間質性肺炎の急性増悪患者4例(男性2例,女性2例・年齢61〜73歳)で,診断はfibrotic nonspecific interstitial pneumonia(f-NSIP)1例,特発性肺線維症(IPF)2例,RA lung/UIP1例であった.また,全例がAaDO2開大,PaO2/F1O2(P/F)比の低下が著しく,挿管されていた.4例中3例(f-NSIP,IPFの1例,RA lung/UIP)でPMX-DHP中の酸素飽和度の上昇を認め,2例(f-NSIP,IPF)で人工呼吸器からの離脱が可能であった.この2例ではIL-10の上昇,IL-8,PAI-1の低下を認め,炎症性サイトカインおよび凝固因子が吸着されたと考えられた

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：(株)メディカルレビュー社  

肺の線維化は種々の疾患で起こるが、現在最も重篤な疾患は特発性肺線維症(Idiopathic Pulmonary Fibrosis:IPF)である。肺の線維化病態には線維芽細胞、筋線維芽細胞が中心的役割を演じているが、それらの細胞の活性にTh1/Th2サイトカインがかかわっていることが知られている。実際にTh1サイトカインであるインターフェロンγ(IFN-γ)は線維芽細胞のコラーゲン産生を抑制することが確認されており、さらにIPFの肺組織におけるTh1/Th2バランスはTh2優位であることも報告されている。そのような背景をもとに、IPFに対するIFN-γ療法について欧米を中心に臨床試験が行われ、今後のIPFの治療戦略として大きな関心が寄せられた。しかし、IFN-γの有効性が期待されるのは%FVCの低下が比較的軽度の患者群であり、現在も%FVC≧55%の患者に限って大規模臨床試験が続けられている。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)医学書院  

DOI： 10.11477/mf.1404100586

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2005240160

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(公社)大気環境学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2004063489

記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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記述言語：日本語   出版者・発行元：(公社)大気環境学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2004063442

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語  

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記述言語：日本語   出版者・発行元：(公社)大気環境学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2003041918

記述言語：日本語   出版者・発行元：(一社)日本毒性学会  

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記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(公社)大気環境学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2003041842

記述言語：日本語   出版者・発行元：(公社)大気環境学会  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2003041843

記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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開催年月日： 2023年3月

記述言語：日本語  

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開催年月日： 2023年3月

記述言語：日本語  

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開催年月日： 2023年2月

記述言語：日本語  

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開催年月日： 2022年11月

記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語  

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開催年月日： 2022年10月

記述言語：日本語  

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記述言語：日本語  

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開催年月日： 2022年9月

記述言語：日本語  

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記述言語：日本語  

49歳男性。12月下旬より乾性咳嗽が出現し、1月上旬より発熱、呼吸困難を自覚したため前医を受診し、レボフロキサシンを処方されるも改善せず、精査加療目的に当院へ入院となった。所見では胸部単純X線およびCTで両側肺野にすりガラス陰影や小葉中心性粒状影が認められた。非定型肺炎と考え、レボフロキサシンを継続投与することで、症状は改善傾向を認めたが、一方で臨床経過や検査結果を踏まえて、過敏性肺炎も疑われ、退院の際には自宅の清掃や羽毛布団の買い替えを行うことを伝えた。そして退院後、入院時に提出していた抗トリコスポロン・アサヒ抗体陽性が判明し、また自宅帰宅後に発熱、乾性咳嗽の再燃を認めたことから、本症例は夏季以外に発症した夏型過敏性肺炎と診断された。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J04260&link_issn=&doc_id=20220831380009&doc_link_id=10.1272%2Fmanms.18.289&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.18.289&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

開催年月日： 2022年5月

記述言語：日本語  

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記述言語：日本語  

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開催年月日： 2022年4月

記述言語：日本語  

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開催年月日： 2022年4月

記述言語：日本語  

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開催年月日： 2022年4月

記述言語：日本語  

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開催年月日： 2022年4月

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記述言語：日本語  

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開催年月日： 2022年1月

記述言語：日本語  

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開催年月日： 2022年

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開催年月日： 2021年12月

記述言語：日本語  

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